A study of the complex genetics of brain development has been undertaken with an emphasis on those genes that cause the most common structural forebrain anomaly in humans, holoprosencephaly (HPE). This malformation of the brain can result from either environmental or genetic causes. It is the aim of these investigations to determine the genes responsible for both normal and abnormal brain development through the study of patients with this disorder. Mutations in six such genes has been shown by us to be responsible for approximately one quarter of familial and sporadic cases of HPE. Other genes either related to the hedgehog pathway or located at defined genetic loci may also contribute to HPE and are the subject of active investigation. We anticipate that many genes important for normal brain development will be identified in the search for genetic causes of HPE. In addition, the aim of these investigations is to identify environmental factors that contribute to HPE. Animal models have shown that low maternal cholesterol causes brain anomalies in some offspring. The findings are now being tested in epidemiological studies where low maternal serum cholesterol during pregnancy is correlated with birth outcome.